The present invention relates to amide derivatives useful as a medicament. The amide derivatives of the present invention are useful as a medicament for treating retinal neurodegenerative disorders and the like.
N-t-Butyl-benzamide, N-t-butyl-4-bromobenzamide, N-t-butyl-4-nitrobenzamide, etc. are known to be useful as a medicament for treating neurodegenerative disorders such as Parkinson""s disease, multiple sclerosis, Alzheimer""s disease and the like (WO 95/28153, WO 96/31462). N-t-Butyl-3-chloro-2-pyridinecarboxamide, N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-2-pyridinecarboxamide, etc. are known to be useful as a herbicide (JP 48-26918(A), JP 60-72803(A), JP 61-151174(A)).
It has been known that N-t-butyl-4-fluorobenzamide, N-t-butyl-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2,5-difluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-5-chloro-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-fluoro-6-iodobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2,6-difluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-chloro-4-fluorobenzamide, etc. were produced as synthetic intermediates (EP 511073, WO 89/06649, J. Org. Chem., 52, 713(1987), J. Org. Chem., 53, 345(1988), EP 538231, U.S. Pat. No. 3,985,889, etc.).
However, these documents do not disclose that the amide derivatives are effective for treating retinal neurodegenerative disorders.
The present invention is intended to provide a medicament for treating retinal neurodegenerative disorders and the like.
The inventors of the present invention have intensively carried out research, and found that amide derivatives are useful as a medicament for treating retinal degenerative disorders and the like. Thus, the present invention has been accomplished.
The present inventions are as follows:
[1] a medicament for treating retinal neurodegenerative disorder comprising a compound of the formula: 
xe2x80x83wherein
Ar is optionally substituted phenyl or optionally substituted aromatic heterocyclic group;
n is 0, 1 or 2;
R1 is hydogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, carbamoyl, alkanoyl or cyano; R2 and R3 are independently optionally substituted alkyl; or any two groups of R1, R2 and R3 may be taken together with the carbon atom adjacent thereto to form cycloalkane, or all of R1, R2 and R3 may be taken together with the carbon atom adjacent thereto to form bicycloalkane or tricycloalkane, wherein the cycloalkane, the bicycloalkane and the tricycloalkane may be substituted optionally;
R4 and R5 are independently hydrogen atom or optionally substituted alkyl;
R6 is hydrogen atom, hydroxy or alkyl;
or a pharmaceutically acceptable salt thereof;
[2] a medicament comprising a compound of the formula: 
xe2x80x83wherein
Ar1 is phenyl substituted by fluorine atom at the 2 or 4 position which may be substituted by further 1 or 2 halogen atoms, or optionally substituted 6-membered heteroaryl;
n, R1, R2, R3, R4, R5 and R6 are as defined above;
or a pharmaceutically acceptable salt thereof; and
[3] a compound of the formula: 
xe2x80x83wherein
Ar2 is a group of the formula: 
xe2x80x83or 6-membered heteroaryl substituted by 1 to 3 halogen atoms;
n, R1, R2, R3 and R6 are as defined above; one of R7 and R8 is fluorine atom; the other is hydrogen atom or halogen atom;
R9 is hydrogen atom or halogen atom; provided that the compound is not the following compound:
N-t-butyl-4-fluorobenzamide,
N-t-butyl-2-fluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2,5-difluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2-fluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-5-chloro-2-fluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2-fluoro-6-iodobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2,6-difluorobenzamide,
N-(2-hydroxy-1,1-dimethylethyl)-2-chloro-4-fluorobenzamide,
N-t-Butyl-3-chloro-2-pyridinecarboxamide and
N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-2-pyridinecarboxamide,
or a pharmaceutically acceptable salt thereof.
xe2x80x9cAromatic heterocyclic groupxe2x80x9d includes, for example, 5- or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Nitrogen atom or sulfur atom constituting heteroaryl may be oxidized. 5-Membered aromatic heterocyclic group includes, for example, the 5-membered aromatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl and the like, and the like. 6-Membered aromatic heterocyclic group includes, for example, the 6-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms, and the like. Typical examples are pyridyl, 1-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
xe2x80x9cHeterocyclic groupxe2x80x9d includes aromatic heterocyclic group, aliphatic heterocyclic group and the like. Aliphatic heterocyclic group includes, for example, 5- or 6-membered aliphatic heterocyclic group containing 1 to 3 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, and the like. 5-Membered aliphatic heterocyclic group includes, for example, the 5-membered aliphatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dioxolanyl and the like, and the like. 6-Membered aliphatic heterocyclic group includes, for example, the 6-membered aliphatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such as piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl and the like, and the like.
The substituent of the substituted phenyl, the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group may be one or more and includes, for example, halogen atom, cyano, nitro, alkyl, alkyl substituted by halogen atom(s), alkoxy, alkoxy substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkyl aminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like.
Preferable substituents of the substituted phenyl include, for example, halogen atom, cyano, nitro, alkyl substituted by halogen atom(s), alkoxy substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like. More preferable examples are the electron-withdrawing groups such as halogen atom, cyano, nitro, trifluoromethyl and the like. Furthermore, preferable is halogen atom, and the most preferable is fluorine atom.
Preferable substituents of the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group include, for example, halogen atom, cyano, nitro, alkyl, alkyl substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like. Particularly preferable is halogen atom.
The number of substituents of the substituted phenyl may be 1, 2 or 3. Preferable examples are 1 and 2, and more preferable is 2. Preferable position of the substitution is the 4 position, and the positions are the 2 and 4 positions if the phenyl is substituted by multiple substituents. The number of substituents of the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group may be 1, 2 or 3. Preferable examples are 1 and 2, and more preferable is 1.
xe2x80x9cAlkylxe2x80x9d includes straight or branched C1-C6 alkyl. Typical examples are methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1,2-dimethylpropyl, hexyl, 3-methylpentyl and the like.
xe2x80x9cAlkoxyxe2x80x9d includes straight or branched C1-C6 alkoxy. Typical examples are methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 3-methylpentoxy and the like.
xe2x80x9cAlkoxyalkoxyxe2x80x9d is the alkoxy substituted by alkoxy. xe2x80x9cAlkoxycarbonylxe2x80x9d is the carbonyl substituted by alkoxy.
xe2x80x9cAlkyl substituted by halogen atom(s)xe2x80x9d and xe2x80x9calkoxy substituted by halogen atom(s)xe2x80x9d are the alkyl and alkoxy substituted by one halogen atom or more. Typical examples are trifluoromethyl, trifluoromethoxy and the like.
xe2x80x9cAlkenylxe2x80x9d includes straight or branched alkenyl having 6 carbon atoms or less. Typical examples are vinyl, allyl, 1-propenyl, 2-butenyl, 5-hexenyl and the like.
xe2x80x9cAlkynylxe2x80x9d includes straight or branched alkynyl having 6 carbon atoms or less. Typical examples are ethynyl, propargyl, 2-butynyl, 5-hexynyl and the like.
xe2x80x9cAlkanoylxe2x80x9d includes, for example, straight or branched alkanoyl having 6 carbon atoms or less. Typical examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-methylbutyryl, hexanoyl and the like.
xe2x80x9cCycloalkylxe2x80x9d includes, for example, C3-C8 cycloalkyl. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In the carbamoyl substituted by alkyl(s), the carbamoyl may be substituted independently by 1 or 2 alkyls.
xe2x80x9cHalogen atomxe2x80x9d includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Preferable examples are fluorine atom, chlorine atom and bromine atom, and particularly preferable is fluorine atom.
xe2x80x9cCycloalkanexe2x80x9d includes, for example, C3-C8 cycloalkane. Typical examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.
xe2x80x9cBicycloalkanexe2x80x9d includes, for example, C7-C10 bicycloalkane. Typical examples are bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like.
xe2x80x9cTricycloalkanexe2x80x9d includes, for example, C7-C13 tricycloalkane. Typical examples are adamantane and the like.
Substituents of the substituted alkyl, the substituted alkenyl, the substituted alkynyl, the substituted cycloalkane, the substituted bicycloalkane and the substituted tricycloalkane include, for example, cycloalkyl, alkoxy, hydroxy, halogen atom, alkoxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, heterocyclic group such as pyrrolidino, piperidino, piperazino, 4-alkylpiperazino, morpholino and the like, and the like. Alkyl, alkenyl, alkynyl, cycloalkane, bicycloalkane and tricycloalkane may be substituted independently by one or more substituents.
Preferable examples of R1, R2 and R3 as indicated in formulae 1, 2 and 3 are optionally substituted alkyl. More preferable are alkyl optionally substituted by hydroxy, and particularly preferable are methyl, ethyl, hydroxymethyl and hydroxyethyl.
Preferable example of R6 as indicated in formulae 1, 2 and 3 is hydrogen atom.
Preferable examples of n as indicated in formulae 1 and 2 are 0 and 1, and particularly preferable is 0.
The pharmaceutically acceptable salts include, for example, salts with inorganic acids and salts with organic acids. Examples of the inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. Examples of the organic acids include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid and the like. The compounds of formula 1, 2 or 3 and the pharmaceutically acceptable salts thereof include their solvates such as the hydrate and the like. The compounds of formula 1, 2 or 3 include their tautomers if the tautomers exist. The compounds of formula 1, 2 or 3 include the mixture of their geometrical isomers and the isolated isomer if the geometrical isomers exist.
The compound of formula 1, 2 or 3 can be produced, for example, by the following methods. In the following description, the production process is illustrated with the compound of formula 1 as a representative. 
wherein R10 is hydrogen atom, protected hydroxy or alkyl; Ar, n, R1, R2, R3, R4, R5 and R6 are as defined above.
Protective groups in the protected hydroxy of R10 include conventionally used protective groups (e.g. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d T. W. Greene, P. M. Wuts John. Wiley and sons 1991, pp. 10-142). Typical examples are substituted silyl such as trimethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl and the like; optionally substituted alkyl such as t-butyl, benzyl, trityl, methoxymethyl, methylthiomethyl, benzyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl and the like, and the like. Preferable are t-butyl, benzyl, trityl, methoxymethyl, tetrahydropyranyl, benzyloxymethyl, methoxyethoxymethyl and the like.
Condensation reaction of the compound of formula 4 and the compound of formula 5 can be carried out by conventional methods in peptide chemistry (xe2x80x9cBasis and Experiment in Peptide Synthesisxe2x80x9d by Nobuo Izumiya et. al., Maruzen, etc.). Typical methods are C-terminal activation methods (e.g. acid halide methods, acid azide methods, mixed acid anhydride methods, activated ester methods, symmetrical acid anhydride methods and the like), methods using coupling agents (e.g. methods using N,Nxe2x80x2-dicyclohexylcarbodiimide and the like), N-terminal activation methods (e.g. isocyanate methods, phosphazo methods, phosphorous ester methods and the like) and the like.
Acid halide methods can be performed, for example, by converting the compound of formula 4 to an acid halide by a conventional method, followed by condensing with the compound of formula 5 in the presence of a base in an inert solvent such as methylene chloride and the like at 0xc2x0 C. to room temperature. The bases include, for example, organic bases such as triethylamine and the like.
Methods using coupling agents can be performed, for example, by condensing the compound of formula 4 with the compound of formula 5 in the presence of coupling agents such as N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride (WSC HCl) and the like, if desired, in the presence of 1-hydroxybenzotriazole (HOBt), in an inert solvent such as methylene chloride, N,N-dimethylformamide (DMF) and the like at 0xc2x0 C. to room temperature. When Ar is optionally substituted pyridyl, the corresponding N-oxide compound can be prepared by oxidation with suitable oxidizing agents after condensation of the compound of formula 4 and the compound of formula 5. The oxidation can be performed by using an oxidizing agent such as hydrogen peroxide and the like in a solvent such as acetic acid, trifluoroacetic acid and the like at room temperature to temperature of reflux.
When R10 is protected hydroxy, the protecting group can be removed by a conventional method. When the protecting group is t-butyl, benzyl, trityl, methoxymethyl, tetrahydropyranyl, benzyloxymethyl, methoxyethoxymethyl and the like, it can be removed by hydrogenation or hydrolysis using an acid catalyst.
The compound of formula 1, 2 or 3 can be purified by a conventional method such as column chromatography, recrystallization and the like. Recrystallization solvent includes, for example, alcohol such as methanol, ethanol, 2-propanol and the like; ether such as diethyl ether and the like; ester such as ethyl acetate and the like; aromatic solvent such as toluene and the like; ketone such as acetone and the like; hydrocarbon solvent such as hexane and the like; water and the like; and mixture thereof. Pharmaceutically acceptable salt of the compound of formula 1, 2 or 3 can be formed by conventional methods, and the salt may be purified by recrystallization or the like.
The compound of formula 1, 2 or 3 or the pharmaceutically acceptable salt thereof may be administered orally or parenterally (e.g. intramuscular injection, intravenous injection, rectal administration by suppository, dermal application for liniments, eye drops or the like). Pharmaceutical forms for oral administration include, for example, tablets, capsules, syrups, suspensions and the like. Pharmaceutical forms for injection include, for example, solutions, emulsions, suspensions and the like. These compositions can be prepared by mixing the active compound with conventional carriers, excipients, binders, stabilizers and the like by conventional methods. Injection may contain buffers, solubilizers, agents for influencing osmotic pressure and the like.
Though the dose and the times for administration varies depending on the grade of the symptoms, the patient""s age, body weight, administration route and the like, the compound is usually administered to an adult in a dose of approximately 1-1000 mg, preferably 10-500 mg per day in one portion or several portions, by the oral route. By injection, the compound is usually administered to an adult in a dose of approximately 0.1-500 mg, preferably 3-100 mg per day in one portion or several portions.
Eye drops can be formed into various formulations. The examples of the eye drops are described in xe2x80x9cTenganzaixe2x80x9d written by Kenji MOTOSE (published by Nanzando, 1984) and xe2x80x9cShin-Sogoyakuzaigaku IIxe2x80x9d edited by Sadao IGUCHI, pp. 77-91 (published by Ishiyaku-Shuppan, 1982). Typical examples of the eye drops include aqueous eye drops (aqueous eye drop solution, sticky eye drop solution, aqueous eye drop suspension, etc.) and non-aqueous eye drops (non-aqueous eye drop solution, non-aqueous eye drop suspension, ophthalmic ointment, etc.) and so on.
Eye drops can be added to by conventional additives, if necessary. Examples of the additive include buffer agents, tonicity agents, thickening agents, preservatives, solubilizing agents, suspending agents, ointment bases, non-aqueous solvents, pH adjusting agents and so on.
Examples of the buffer agents include boric acid, sodium dihydrogenphosphate, disodiumhydrogenphosphate, borax, sodium carbonate, sodium hydrogencarbonate, citric acid, sodium citrate, acetic acid, sodium acetate, sodium carbonate and so on.
Examples of the tonicity agents include sodium chloride, boric acid, sodium nitrate, potassium nitrate, potassium chloride and so on.
Examples of the thickening agents include methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxyethylcellulose, chondroitin sulfuric acid, polyvinylpyrrolidone, gelatine, glycerin, macrogolum and so on.
Examples of the preservatives include benzalkonium chloride, phenymercuric nitrate, phenymercuric acetate, thimerosal, chlorhexidine acetate, chlorobutanol, phenylethyl alcohol, paraoxybenzoate esters, sodium dehydroacetate, cetylpyridinium chloride, alkylpolyaminoethylglycine, sorbic acid and its salts and so on.
Examples of the solubilizing agents include sodium carboxymethylcellulose, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol monooleate and so on.
Examples of the suspending agents include polysorbate 80, aluminum monostearate and so on.
Examples of the ointment bases include vaseline, purified lanolin, zeren, plastibase and so on.
Examples of the non-aqueous solvents include vegetable oil, liquid paraffin, propylene glycol, mineral oil, xcex2-octyldodecanol and so on.
Examples of the pH adjusting agents include sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, citric acid, phosphoric acid, acetic acid and so on.
Though the usage and dose of the eye drops of the invention varies depending on the concentration of the medicament, the patient""s symptoms and age and so on, the eye drops are usually administrated in 1 to 2 drops per one time and 1 to 6 times per day. A suitable amount of ophthalmic ointment is usually applied in saccus conjunctivae in 1 to 2 times per day.